Researchers Reverse Rare Autism Disorder in Mice

One out of about every 10,000 girls is born with a mutation that causes autism-like behavior, stunts growth, and impairs the ability to think, sleep, and even breathe. There is no cure for the condition, known as Rett syndrome, but a new study of mice proposes that bone marrow transplants that increase a certain type of immune cell in the brain can lessen some symptoms. Researchers say the findings may be an important clue to the mechanisms of the disease, but they caution that much more work is needed to identify the treatment potential.

Rett syndrome results from mutations in a gene on the X chromosome called MECP2, which regulates the activity of other genes. Researchers replaced the mice’s immune systems by first exposing four-week-old mice to radiation to kill off their existing immune cells — including microglia — and then injecting them with bone-marrow cells with a working copy of MECP2. Stem cells in bone marrow form the immune system, including microglia cells.

Male Rett mice, with no working copy of MECP2, usually die within two months, but the ones that got bone marrow from healthy mice lived up to a year, Jonathan Kipnis, a neuroscientist at the University of Virginia School of Medicine in Charlottesville, who led the study says. The treated mice breathed easier, walked better and gained more weight compared with untreated mice. Female mice with just one working copy of MECP2 develop Rett symptoms later than male mice, but a bone-marrow transplant improved gait, breathing and weight gain for them, too.

The oldest of the treated mice has now lived almost a year, neuroimmunologists Noël Derecki who also worked on the study says. “This seems to stop the disease in its tracks.”

“If we show the immune system is playing a very important role in Rett patients and we could replace it in a safe way, we may develop some feasible therapies in the future,” says Kipnis.

Kipnis hypothesizes that microglia from Rett mice have trouble clearing cellular rubbish in the brain, making it more difficult for their neurons to work properly. Fixing MECP2 mutations with gene therapy is well beyond current technology, Kipnis notes. “But if we can improve the environment by adding microglia, which is feasible, we may be able to attenuate some aspects of the disease.” He’s not advocating clinical trials anytime soon, though. Although bone marrow transplants are already performed on children with leukemia and other cancers, the procedure carries a high risk of serious, and even fatal, side effects.

Less drastically, Kipnis thinks that the disease could also be treated with drugs that improve microglia function. Girls with Rett syndrome have one working copy of MECP2, so half of their microglia may work.

Frauke Zipp, a neuro-immunologist at the Johannes Gutenberg University Mainz in Germany, agrees that a clinical trial of cell transplantation to treat Rett syndrome is far afield, but not inconceivable if additional research pins down their role in disease.

“These findings contribute to the idea that Rett syndrome is a very complicated disorder involving multiple cell types and systems,” adds Gail Mandel, a neuroscientist at Oregon Health Sciences University near Portland. Some form of gene therapy may be a way of fixing all these different problems, she says.